chr11-18279812-G-A

Position:

chr11-18279812-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_181507.2(HPS5):c.*70C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,440,388 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00098 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 19 hom. )

Consequence

HPS5
NM_181507.2 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.737

Variant links:

Genes affected

HPS5 (HGNC:17022): (HPS5 biogenesis of lysosomal organelles complex 2 subunit 2) This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. This protein interacts with Hermansky-Pudlak syndrome 6 protein and may interact with the cytoplasmic domain of integrin, alpha-3. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 5. Multiple transcript variants encoding two distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

HPS5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 11-18279812-G-A is Benign according to our data. Variant chr11-18279812-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 303864.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000979 (149/152272) while in subpopulation SAS AF= 0.00477 (23/4822). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 72 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPS5	NM_181507.2 linkuse as main transcript	c.*70C>T		3_prime_UTR_variant	23/23	ENST00000349215.8

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPS5	ENST00000349215.8 linkuse as main transcript	c.*70C>T	3_prime_UTR_variant	23/23	1	NM_181507.2	P1	Q9UPZ3-1
HPS5	ENST00000396253.7 linkuse as main transcript	c.*70C>T	3_prime_UTR_variant	22/22	1			Q9UPZ3-2
HPS5	ENST00000438420.6 linkuse as main transcript	c.*70C>T	3_prime_UTR_variant	22/22	1			Q9UPZ3-2
HPS5	ENST00000537258.1 linkuse as main transcript	c.*123C>T	3_prime_UTR_variant	6/6	5

Frequencies

GnomAD3 genomes

AF:

0.000979

AC:

149

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.0239

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.000955

GnomAD4 exome

AF:

0.00142

AC:

1834

AN:

1288116

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

1093

AN XY:

649306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000331

Gnomad4 AMR exome

AF:

0.000274

Gnomad4 ASJ exome

AF:

0.0246

Gnomad4 EAS exome

AF:

0.000489

Gnomad4 SAS exome

AF:

0.00788

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000376

Gnomad4 OTH exome

AF:

0.00273

GnomAD4 genome

AF:

0.000979

AC:

149

AN:

152272

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.0239

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000902

Hom.:

Bravo

AF:

0.00104

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hermansky-Pudlak syndrome 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.9

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over